LGD-5552, an Antiinflammatory Glucocorticoid Receptor Ligand with Reduced Side Effects, in Vivo

Abstract

Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.

Selective Glucocorticoid Receptor modulators

“…LGD5552-((5Z)-5-[(2-Fluoro-3-methylphenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H- [1]benzopyrano [3,4-f]quinolin-9-ol) is a non-steroidal compound of molecular weight similar to prednisolone but differing in its ring saturation as well as in its substituents [50].…”

Selective Glucocorticoid Receptor Agonists for the Treatment of Inflammatory Bowel Disease: Studies in Mice with Acute Trinitrobenzene Sulfonic Acid Colitis

“…In summary, although controversial, but on the basis of additional publications that report the successful application of different GR modulators (Owen et al, 2007;Schä cke et al, 2007;López et al, 2008), the dissociation concept of SEGRAs still has promising potential for the treatment of inflammatory conditions such as IBD. Therefore, in a TNBS model of acute colitis we investigated the GR agonists CpdA and ZK216348, which are classified as SEGRAs.…”

The Future of Steroid Therapy in Inflammatory Disease

“…Of these Compound A (CpdA) was the earliest to be identified and was first isolated from the Namibian shrub (Salsola tuberculatiformis). This non-steroidal compound when investigated was found to bind atypically to the GR in ligand binding essays but with high affinity, and was thought it may be using different coupling points in the Ligand binding domain of the GR or by inducing a unique conformation of the GR which is not yet understood [20][21][22][23][24].…”

“…As such this is a very interesting compound which can be used as a platform to study future SERMs and is being suggested for phase 1 clinical trials in an MS model [21]. Table 1: List of known SGRMs/SERMS and their profile of action [19][20][21][22][23].…”

“…These in vivo results within a rodent model of EAE (autoimmune encephalitis) it was found that LGD-5552 at doses of 1-3mg/kg had no effect on mean arterial blood pressure (MABP) but produced even greater efficacy than prednisolone and completely ameliorated disease (mean disease score=0) with no signs of motor impairment (p=0.0002) and no changes in body weight. As such going forward this remains a safer alternative to current GC based treatment in models of disease [20].…”